This proposal for a K24 renewal will continue to : (1) provide protected time and support to Dr. Ayappa while she mentors graduate students, post-doctoral fellows and junior faculty pursuing careers in patient-oriented research of sleep disorders; (2) conduct clinical research in patients with sleep disordered breathing (SDB) including obstructive sleep apnea (OSA) and (3) augment her capabilities to conduct patient-oriented research and mentoring. Dr Ayappa is actively involved in research in pathophysiology, diagnosis, treatment and outcomes of SDB that provides research opportunities for mentoring. Obstructive sleep apnea (OSA) is a highly prevalent disorder affecting 15-50% of the US population. Untreated OSA has significant morbidity and mortality including cardiovascular and neurocognitive impairment. Multiple ongoing projects will provide mentoring and patient oriented research opportunities for Dr. Ayappa's mentees. The first project will examine the mechanistic pathways involved in the high prevalence of OSA in World Trade Center (WTC) dust exposed subjects. We recently identified chronic rhinosinistis (CRS) as an independent risk factor for OSA in this population that was associated with inflammation, but was not due to increased nasal resistance. We will (i) test if damage to the upper airway sensory apparatus contributes to OSA in WTC responders with CRS and (ii) identify predominant OSA phenotypic traits in WTC responders and compare them to OSA patients from a sleep clinic. (U01OH011481) The second project (funded by Fisher & Paykel Healthcare) involves development and testing of novel algorithms for non-invasive ventilation in patients with obesity hypoventilation syndrome. These include application of pressures exclusively during sleep (for comfort) and automatic titration of pressures to ensure efficacy. The third area of research in collaboration with Ricardo Osorio, MD examines the relationship between sleep and Alzheimer's Disease (AD). We will extend our prior work in our well characterized longitudinal cohort of cognitively normal older adults in whom we recently demonstrated that OSAwas associated with markers of increased amyloid burden over a 2 year follow-up (1R01HL118624, R01AG056031). We will follow these subjects for an additional 4 years to test the longitudinal effects of slow wave sleep and OSA severity on amyloid deposition. We will also examine (R01AG056531) whether sleep disturbances, which are more common among African-Americans when compared to whites, are one of the factors that explain increases in amyloid burden. The activities outlined in the proposal are directed toward Dr Ayappa's career development. The mentoring work will address the need for new researchers in sleep medicine. The experimental work provides learning opportunities for mentees and is relevant for understanding the physiology of OSA and its outcomes, its diagnosis and treatment with potential for improving health and quality of life in millions of patients who suffer from sleep apnea.